DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993

NDA 208271
NDA APPROVAL
Salix Pharmaceuticals
Attention: Mary Harrell
Director, Regulatory Affairs
400 Somerset Corporate Boulevard
Bridgewater, NJ 08807

Dear Mary Harrell:
Please refer to your New Drug Application (NDA) dated June 19, 2015, received June 19, 2015,
submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
Relistor (methylnaltrexone bromide) 150 mg tablets.
We acknowledge receipt of your major amendments dated February 5, 2016, February 10, 2016,
March 10, 2016, March 16, 2016 and March 17, 2016, which extended the goal date by three
months to July 19, 2016.
This new drug application provides for the use of Relistor (methylnaltrexone bromide) 150 mg
tablets for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain.
We have completed our review of this application, as amended. It is approved, effective on the
date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
WAIVER OF HIGHLIGHTS SECTION
We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
prescribing information. This waiver applies to all future supplements containing revised
labeling unless we notify you otherwise.
CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter, submit the content of
labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
automated drug registration and listing system (eLIST), as described at
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
of labeling must be identical to the enclosed labeling (text for the package insert, text for the
patient package insert, Medication Guide). Information on submitting SPL files using eLIST
may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs

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and As, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM072392.pdf.
The SPL will be accessible via publicly available labeling repositories.
CARTON AND IMMEDIATE CONTAINER LABELS
Submit final printed carton and immediate container labels that are identical to the carton and
immediate container labels submitted on June 10, 2016, as soon as they are available, but no
more than 30 days after they are printed. Please submit these labels electronically according to
the guidance for industry Providing Regulatory Submissions in Electronic Format – Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
(June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually
mounted on heavy-weight paper or similar material. For administrative purposes, designate this
submission “Final Printed Carton and Container Labels for approved NDA 208271.
Approval of this submission by FDA is not required before the labeling is used.
Marketing the product(s) with FPL that is not identical to the approved labeling text may render
the product misbranded and an unapproved new drug.
MARKET PACKAGE
Please submit one market package of the drug product when it is available to the following
address:
Lawrence Allan
Food and Drug Administration
Center for Drug Evaluation and Research
White Oak Building #22, Room: 5353
10903 New Hampshire Avenue
Silver Spring, Maryland
Use zip code 20903 if shipping via United States Postal Service (USPS).
Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
REQUIRED PEDIATRIC ASSESSMENTS
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
administration are required to contain an assessment of the safety and effectiveness of the
product for the claimed indication(s) in pediatric patients unless this requirement is waived,
deferred, or inapplicable.
We are waiving the pediatric study requirement for this application because the necessary studies
are impossible or highly impracticable. This is due to the low number of pediatric patients with

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chronic opioid use for chronic non-cancer pain and therefore few patients with OIC associated
with chronic opioid use.
POSTMARKETING REQUIREMENTS UNDER 505(o)
Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
biological product applications to conduct postmarketing studies and clinical trials for certain
purposes, if FDA makes certain findings required by the statute.
We have determined that an analysis of spontaneous postmarketing adverse events reported
under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious
risk of major adverse cardiovascular events.
Furthermore, the new pharmacovigilance system that FDA is required to establish under section
505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
Therefore, based on appropriate scientific data, FDA has determined that you are required to
conduct the following:
3046 – 1: A post-marketing, observational epidemiologic study comparing oral Relistor
(methylnaltrexone bromide) to other treatments of opioid induced constipation in patients
with chronic non-cancer pain. The study’s primary outcome is a composite of major
adverse cardiovascular events (MACE): cardiovascular (CV) death, nonfatal myocardial
infarction, and nonfatal stroke. Secondary outcomes include, but are not limited to, CV
death, nonfatal myocardial infarction, and nonfatal stroke separately. Specify concise
case definitions and validation algorithms for the primary and secondary outcomes.
Justify the choice of appropriate comparator population(s) and estimated background
rate(s) relative to oral Relistor (methylnaltrexone bromide)-exposed patients; clearly
define the primary comparator population for the primary objective. Design the study
around a testable hypothesis to assess, with sufficient sample size and power, MACE risk
among oral Relistor (methylnaltrexone bromide) users relative to comparator(s)
considering important potential confounders including lifestyle risk factors and over the
counter (OTC) medications with potential for cardiovascular effects, with a pre-specified
statistical analysis method. For the oral Relistor (methylnaltrexone bromide)-exposed
and comparator(s), clearly define the new user clean period, including any exclusion and
inclusion criteria. Ensure an adequate number of patients with at least 12 months of oral
Relistor (methylnaltrexone bromide) exposure at the end of the study.
The timetable you submitted on May 20, 2016, states that you will conduct this study according
to the following schedule:
Final Protocol Submission:
Study Completion:
Final Report Submission:

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July 2017
April 2024
July 2025

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Submit the protocol(s) to your IND 067452, with a cross-reference letter to this NDA. Submit all
final report(s) to your NDA. Prominently identify the submission with the following wording in
bold capital letters at the top of the first page of the submission, as appropriate: “Required
Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report Under
505(o),” “Required Postmarketing Correspondence Under 505(o).”
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
study or clinical trial required under this section. This section also requires you to periodically
report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
report annually on the status of any postmarketing commitments or required studies or clinical
trials.
FDA will consider the submission of your annual report under section 506B and 21
CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
include a report on the status of any study or clinical trial otherwise undertaken to investigate a
safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
result in enforcement action.
PROMOTIONAL MATERIALS
You may request advisory comments on proposed introductory advertising and promotional
labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
proposed materials in draft or mock-up form with annotated references, and the package insert,
Medication Guide, and patient PI (as applicable) to:
OPDP Regulatory Project Manager
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Prescription Drug Promotion
5901-B Ammendale Road
Beltsville, MD 20705-1266
Alternatively, you may submit a request for advisory comments electronically in eCTD format.
For more information about submitting promotional materials in eCTD format, see the draft
Guidance for Industry (available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM443702.pdf ).
As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
2253. Form FDA 2253 is available at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.

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Information and Instructions for completing the form can be found at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
more information about submission of promotional materials to the Office of Prescription Drug
Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
REPORTING REQUIREMENTS
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
If you have any questions, call Lawrence Allan, Regulatory Project Manager, at (240) 402 –
2786.

Sincerely,
{See appended electronic signature page}
Donna Griebel, MD
Director
Division of Gastroenterology and Inborn
Errors Products
Office of Drug Evaluation III
Center for Drug Evaluation and Research

Enclosure(s):
Content of Labeling
Carton and Container Labeling

Reference ID: 3961040

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------DONNA J GRIEBEL
07/19/2016

Reference ID: 3961040
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